Due to the differences among the genetic animals models being maintained, used and developed in 5 of the 6 IMA sites, a separate U-24 application to support genetic animal models is being submitted from each site. Dr. John Crabbe, Professor of Behavioral Neuroscience, Oregon Health Sciences University (OHSU), will serve as coordinator of the overall Genetic Animal Models Core described in this application. The major goal of the GAMC is to integrate animal model development availability and usage across sites. Genetic animal models have been a major staple of alcohol research since the first were developed in the late 1940?s. it has been known for many years that animals experienced with alcohol self-administration and/or dependent on alcohol will increase their intake for a relatively short period of time after a period of withdrawal. However, these and other existing models are not yet optimal. Generally, the magnitude and architecture of the response does not convincingly display either gross excess or obvious loss of control that extends for a long time after the initial period of intoxicating self-administration. Virtually nothing is known about the genetic predisposition to self-administration potentiated by any of the above manipulations. Little to nothing has been done to characterize any of these phenomena in existing mouse genetic models of high or low ethanol drinking or high or low withdrawal. The general goals of the GAMC are to facilitate the development of more robust phenotypes and genotypes; facilitate the exploration of gene X environment interactions and facilitate development of novel genetic technology to explore the two-hit hypothesis, i.e. that at least two clusters of genes must be dysregulated to produce abusive self-administration; to achieve coordinated genetic animal model utilization and development across IMA sites and Cores; and to provide relevant data to the Informatics Core. At the Austin site, specific emphasis is placed on development of novel mutant mice with deletions or mutations of single genes. Construction of mutant mice required by other INIA projects will use an inbred C57 background. Mutant mice will be tested for alcohol phenotypes at the Austin site.